Block coordinate descent algorithm improves variable selection and estimation in error-in-variables regression.

Medical research increasingly includes high-dimensional regression modeling with a need for error-in-variables methods. The Convex Conditioned Lasso (CoCoLasso) utilizes a reformulated Lasso objective function and an error-corrected cross-validation to enable error-in-variables regression, but requires heavy computations. Here, we develop a Block coordinate Descent Convex Conditioned Lasso (BDCoCoLasso) algorithm for modeling high-dimensional data that are only partially corrupted by measurement error. This algorithm separately optimizes the estimation of the uncorrupted and corrupted features in an iterative manner to reduce computational cost, with a specially calibrated formulation of cross-validation error. Through simulations, we show that the BDCoCoLasso algorithm successfully copes with much larger feature sets than CoCoLasso, and as expected, outperforms the naïve Lasso with enhanced estimation accuracy and consistency, as the intensity and complexity of measurement errors increase. Also, a new smoothly clipped absolute deviation penalization option is added that may be appropriate for some data sets. We apply the BDCoCoLasso algorithm to data selected from the UK Biobank. We develop and showcase the utility of covariate-adjusted genetic risk scores for body mass index, bone mineral density, and lifespan. We demonstrate that by leveraging more information than the naïve Lasso in partially corrupted data, the BDCoCoLasso may achieve higher prediction accuracy. These innovations, together with an R package, BDCoCoLasso, make error-in-variables adjustments more accessible for high-dimensional data sets. We posit the BDCoCoLasso algorithm has the potential to be widely applied in various fields, including genomics-facilitated personalized medicine research.

Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci.

Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10(-7)). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10(-8)), SLC6A14 (p = 1.12x10(-10)) and SLC26A9 (p = 4.48x10(-5)) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10(-4)). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies.

Clinical impact of 3-level anterior cervical decompression and fusion (ACDF) on the occipito-atlantoaxial complex: a retrospective study of patients who received a zero-profile anchored spacer versus cage-plate construct.

PURPOSE: To evaluate changes in the sagittal parameters of the occipito-atlantoaxial complex after three-level anterior cervical decompression and fusion (ACDF) and identify the influential factors by comparing ACDF with a zero-profile anchored spacer (ACDF-Z) versus a cage-plate construct (ACDF-P). METHODS: The cohort comprised 106 patients who underwent three-level contiguous ACDF-Z or ACDF-P for cervical radiculopathy and/or myelopathy. Standing, flexion, and extension radiographs of cervical spine were obtained preoperatively, and 3 and 12 months postoperatively. The assessed cervical sagittal parameters were the platform angle of the axis, Cobb angle, and range of motion (ROM) of C2⁃7, C0⁃1, and C1⁃2. RESULTS: In both the ACDF-Z and ACDF-P groups, the Cobb angle of the upper cervical spine decreased and the C0-1 ROM increased from preoperatively to 3 and 12 months postoperatively (P < 0.01). The alignment restoration was lost at 12 months compared with 3 months in the ACDF-Z group, but not in the ACDF-P group (P < 0.01). The ACDF-P group showed more loss of C2-7 ROM and more compensatory changes in C0-2 ROM than the ACDF-Z group (P < 0.05). CONCLUSION: The Cobb angle decreased and ROM increased significantly as compensatory changes of the atlantooccipital or atlantoaxial joint after both types of ACDF, which may accelerate degeneration. The zero-profile anchored spacer had less impact on the occipito-atlantoaxial complex but was worse at maintaining the alignment restoration, which were contrary to the cage-plate construct. Surgeons should be aware of the impact of multi-level ACDFs on the occipito-atlantoaxial complex.

An Unrecognized Ligament and its Ossification in the Craniocervical Junction: Prevalence, Patient Characteristics, and Anatomic Evidence.

BACKGROUND: In the craniocervical junction, the ligaments between the anterior foramen magnum and the anterior arch of the atlas are not well defined, and ossification of the ligaments in this region has rarely been reported. Characterizing the anatomy and ossification of these ligaments may help in the diagnosis and treatment of disorders in this region. QUESTIONS/PURPOSES: (1) What is the prevalence of an unrecognized ossification at the craniocervical junction in patients with cervical spine disorders, and what are the patient characteristics associated with this ossification? (2) Do patients with this ossification have a greater risk of ossification of other structures at the craniocervical junction or cervical spine? (3) Is there an unreported ligament at this ossified site? METHODS: We conducted a retrospective study of 578 hospitalized patients who underwent CT for cervical spine disorders between January 2016 and July 2020. Based on the inclusion criteria, 11% (66 of 578) were excluded because of a cervical or craniocervical tumor, deformity, infection, fracture or dislocation, or prior surgery, leaving 89% (512 of 578) for analysis. These 512 patients had diagnoses of cervical radiculopathy, cervical myelopathy, cervical spondylotic amyotrophy, cervical spinal cord injury without a radiographic abnormality, or axial neck pain. Their mean age was 57 years (range 22-90 years), and 60% of the patients were men. Patient characteristics including age, gender, and diagnosis were retrieved from a longitudinally maintained institutional database. CT images were used to assess the presence of a previously unrecognized ossification and ossification of other structures in the craniocervical junction and cervical spine, including the posterior longitudinal ligament, anterior longitudinal ligament, nuchal ligament, ligamentum flavum, transverse ligament, and apical ligament, as well as diffuse idiopathic skeletal hyperostosis (DISH). The association between these structures was also assessed. This unreported ossification was called the capped dens sign. It was defined and graded from 1 to 3. Grade 3 was defined as the typical capped dens sign. Cervical spine MRI was used to assess whether there was an unreported structure in the same region as where the capped dens sign was detected on CT images. In the database of a recent study, there were 33 patients younger than 41 years. Nine percent (three of 33) were excluded because they did not have cervical spine MRI. MRIs of the remaining 30 patients were assessed. Their mean age was 35 years (range 22-40 years), and 58% were men. All cervical spine CT images and MRIs were reviewed by one senior spine surgeon and one junior spine surgeon twice with a 2-week interval. Blinding was accomplished by removing identifying information from the radiographs and randomly assigning them to each examiner. Any discrepancy with respect to the grade of the capped dens sign was adjudicated by a third blinded senior spine surgeon. Intrarater and interrater reliabilities were assessed by calculating weighted kappa statistics. No ligament or membrane was reported at this site. MRI is not sensitive to identify thin tissue in this region, especially when severe degeneration has occurred. A cadaveric study was conducted to discover a potential ligament between the inferior margin of the foramen magnum and the anterior arch of the atlas, as prompted by the newly discovered ossification in the clinical analysis of this study. Six embalmed human cadaveric craniocervical regions (three male and three female cadavers; median age 56 years, range 45-78 years) were dissected by a senior anatomist and a senior anatomy technician. A mid-sagittal section of the craniocervical junction was created, allowing us to explore the interval between the anterior foramen magnum and anterior arch of the atlas. A histologic analysis was conducted in two of the six cadavers (a male cadaver, 45 years; and a female cadaver, 51 years). Slides were made with 4-µm sections and stained with hematoxylin and eosin. RESULTS: A novel capped dens sign was detected in 39% (198 of 512) of the patients and the most typical capped dens sign was detected in 19% (96 of 512) of patients. The prevalence of this sign was the highest in patients with cervical spondylotic amyotrophy (12 of 25 patients). The prevalence of ossification of the anterior longitudinal ligament, ligamentum nuchae, and apical ligament, as well as DISH, was higher in patients with a capped dens sign than in those without (p = 0.04, p < 0.001, p < 0.001, and p = 0.001, respectively). The capped dens sign was identified in 69% (18 of 26) of the patients with DISH. A thin and short band-like structure or osteophyte was detected on MRI in 87% (26 of 30), in the same region as the capped dens sign. In the cadaveric study, an unreported, distinct ligamentous structure was identified at this ossified site. It originated from the posterosuperior rim of the anterior arch of the atlas to the inferior margin of the foramen magnum, which we called the inter-atlanto-occipital ligament. It was found in all six dissected craniocervical junctions. The histologic analysis revealed dense connective tissue. CONCLUSION: More than one-third of the patients in this series demonstrated CT evidence of a previously unrecognized ossification in the craniocervical junction, which we called the capped dens sign. Anatomic evidence of this sign, which was a previously unidentified ligament, was also newly discovered in this region. This study was conducted among Asian patients and specimens. Further studies among diverse ethnic groups may be needed to generalize the results. An additional well-designed prospective study will be needed to provide further evidence regarding the potential pathophysiology and clinical relevance of the capped dens sign. Furthermore, the cadaveric analysis in this study was only a preliminary report of the ligament; further biomechanical research is needed to investigate its function. CLINICAL RELEVANCE: Knowledge of this novel ligament may improve the diagnosis and treatment of craniocervical stability and dislocation. Ossification of this ligament is correlated with age, cervical spondylotic amyotrophy, and DISH. We wonder whether patients with cervical degenerative disorders who also have a capped dens sign may be at risk for the formation of osteophytes of an uncovertebral joint, which may result in palsy of the upper limb muscles. The capped dens sign may be the craniocervical manifestation of DISH. This possible association between the capped dens sign and DISH should be considered when performing surgery on patients with the capped dens sign.

SWAN scale for ADHD trait-based genetic research: a validity and polygenic risk study.

BACKGROUND: Population-based samples with valid, quantitative and genetically informative trait measures of psychopathology could be a powerful complement to case/control genetic designs. We report the convergent and predictive validity of the parent- and self-report versions of the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scale (SWAN). We tested if SWAN scores were associated with ADHD diagnosis, ADHD polygenic risk, as well as traits and polygenic risk for disorders that co-occur with ADHD: anxiety and obsessive-compulsive disorder (OCD). METHODS: We collected parent- and self-report SWAN scores in a sample of 15,560 children and adolescents (6-17 years) recruited at a science museum (Spit for Science sample). We established age and sex norms for the SWAN. Sensitivity-specificity analyses determined SWAN cut-points that discriminated those with and without a reported ADHD diagnosis. These cut-points were validated in a clinic sample (266 ADHD cases; 36 controls). Convergent validity was established using the Conners' parent- and self-report scales. Using Spit for Science participants with genome-wide data (n = 5,154), we tested if low, medium and high SWAN scores were associated with polygenic risk for ADHD, OCD and anxiety disorders. RESULTS: Parent- and self-report SWAN scores showed high convergent validity with Conners' scales and distinguished ADHD participants with high sensitivity and specificity in the Spit for Science sample. In a clinic sample, the Spit for Science cut-points discriminated ADHD cases from controls with a sensitivity of 84% and specificity of 92%. High SWAN scores and scores above the Spit for Science cut-points were significantly associated with polygenic risk for ADHD. SWAN scores were not associated with polygenic risk for OCD or anxiety disorders. CONCLUSIONS: Our study supports the validity of the parent- and self-report SWAN scales and their potential in ADHD population-based genetic research.

Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

Influence of Blood Pressure on Acute Cervical Spinal Cord Injury Without Fracture and Dislocation: Results From a Retrospective Analysis.

OBJECTIVE: The objective of this study was to investigate the influence of blood pressure on the severity and functional recovery of patients with acute cervical spinal cord injury (SCI) without fracture and dislocation. METHODS: A retrospective case control study analyzed the data of 40 patients admitted to our orthopedics department (Beijing Tiantan Hospital, Capital Medical University) from January 2013 to February 2021. They were diagnosed as acute cervical SCI without fracture and dislocation. Gender, age, height, weight, history of hypertension, postinjury American Spinal Injury Association grade, postinjury modified Japanese Orthopaedic Association (mJOA) score, postoperative mJOA score, 1-year follow-up mJOA score, preoperative mean arterial pressure (MAP), intramedullary T2 hyperintensity, and hyponatremia were collected. The patients were divided into groups and subgroups based on their history of hypertension and preoperative MAP. The effects of history of hypertension and preoperative MAP on the incidence of T2 hyperintensity, hyponatremia, the improvement rate of the postoperative mJOA and 1-year follow-up mJOA scores were analyzed. RESULTS: Patients with history of hypertension had a lower incidence of intramedullary T2 hyperintensity than patients without history of hypertension (P < 0.05). Patients with history of hypertension and patients with a higher preoperative MAP had better neurological recovery at 1 year of follow-up (P < 0.05). CONCLUSIONS: Blood pressure has great influence on acute cervical SCI without fracture and dislocation. Maintaining a higher preoperative MAP is advantageous for better recovery after SCI. Attention should be paid to the dynamic management of blood pressure to avoid the adverse effects of hypotension after SCI.

Depression and anxiety in cervical degenerative disc disease: Who are susceptible?

Background: Pre-operative depression and anxiety are associated with poorer patient-reported outcomes following cervical spine surgery. Identification of and interventions for these disorders are key to preventing related negative effects. However, most spine surgeons do not routinely evaluate mental health disorders. Few studies have investigated which patients with cervical degenerative disc diseases (CDDD) are susceptible to depression and anxiety. Objective: To determine the factors associated with depression and anxiety in patients with CDDD. Methods: Three hundred twelve patients with CDDD were recruited in this cross-sectional case-control study. Patients underwent a structured interview to acquire demographic and clinical characteristic information, which included the Neck Disability Index (NDI), modified Japanese Orthopedic Association (mJOA), and Visual Analog Scale (VAS) for neck/arm pain. Depression and anxiety were evaluated using the Zung Self-Rating Depression and Anxiety Scales. Univariate and multivariate logistic regression analyses were used to identify factors associated with depression and anxiety. Results: Of all patients, 102 (32.7%) had depression and 92 (29.5%) had anxiety. Two hundred six (66.0%) patients with neither depression nor anxiety were defined as the control group. Univariate analysis indicated that gender, educational level, occupation type, Charlson comorbidity index, symptom duration, symptomatology, surgery history, NDI, mJOA, VAS-neck, and VAS-arm scores were associated with depression and anxiety (except for symptom duration for anxiety). Multivariate logistic regression analysis indicated that females [odds ratio (OR) 1.81, 95% confidence interval (CI) 1.01-3.23], physical work (OR 2.06, 95% CI 1.16-3.65), poor mJOA score (ORmoderate 2.67, 95% CI 1.40-5.07; ORsevere 7.63, 95% CI 3.85-15.11), and high VAS-neck score (OR 1.24, 95% CI 1.11-1.39) were independent risk factors for depression. Physical work (OR 1.84, 95% CI 1.01-3.35), poor mJOA score (ORmoderate 2.66, 95% CI 1.33-5.33; ORsevere 9.26, 95% CI 4.52-18.99), and high VAS-neck score (OR 1.34, 95% CI 1.19-1.51) were independent risk factors for anxiety. Conclusion: Approximately one-third of patients with CDDD had depression or anxiety. Patients who engaged in heavy work and had severe symptoms (poor mJOA and high VAS-neck scores) are susceptible to depression and anxiety. Additionally, female patients are susceptible to depression. Our findings may help identify CDDD patients with depression and anxiety in clinical practice.

Cervical Extensor Muscles Play the Role on Malalignment of Cervical Spine: A Case Control Study With Surface Electromyography Assessment.

STUDY DESIGN: A case control study. OBJECTIVE: The aim of this study was to identify the potential impact of cervical spine malalignment on muscle parameters. SUMMARY OF BACKGROUND DATA: Muscular factors are associated with cervical alignment. Nevertheless, only muscle dimensions or imaging changes have been evaluated, function of cervical muscles has scarcely been investigated. METHODS: Thirty-four patients diagnosed as cervical spine degeneration associated with cervical malalignment and 32 control subjects were included in this case control study. Visual analogue scale (VAS) and the neck disability index (NDI) were used. The sagittal alignment parameters and cervical range of motion (ROM) were measured on cervical spine lateral radiographs, included C2-C7 lordosis, C2-C7 sagittal vertical axis (C2-C7 SVA), cervical gravity-sagittal vertical axis (CG-SVA), T1-Slope, and spinal canal angle (SCA). Surface electromyography (SEMG)-based flexion-relaxation ratio (FRR) was measured. RESULTS: The result showed VAS score of the neck significantly lower in controls (P<0.05), C2-C7 lordosis, C2-C7 SVA, CG-SVA, T1-Slope and ROM showed significantly different (P<0.001) between malalignment group and control group, FRR of splenius capitis (FRRSpl) and upper trapezius (FRRUTr) of the malalignment group were lower than in the control group, which correlated well with NDI (rSpl = -0.181 rUTr = -0.275), FRRSpl correlated well with VAS (rSpl = -0.177). FRRSpl correlated strongly with C2-C7 SVA (r = 0.30), CG-SVA (r = 0.32), T1-Slope (r = 0.17), ROM (r = 0.19), FRRUTr correlated with C2-C7 lordosis (r = -0.23), CG-SVA (r = 0.19), T1-Slope (r = 0.28), ROM (r = 0.23). CONCLUSION: Cervical malalignment patients had more tensional posterior cervical muscle and poor muscle functions. CG-SVA showed advantages in evaluating cervical malalignment.Level of Evidence: 3.

Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder.

Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10-8). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p's < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (rg = 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery.

Improving imputation in disease-relevant regions: lessons from cystic fibrosis.

Does genotype imputation with public reference panels identify variants contributing to disease? Genotype imputation using the 1000 Genomes Project (1KG; 2504 individuals) displayed poor coverage at the causal cystic fibrosis (CF) transmembrane conductance regulator (CFTR) locus for the International CF Gene Modifier Consortium. Imputation with the larger Haplotype Reference Consortium (HRC; 32,470 individuals) displayed improved coverage but low sensitivity of variants clinically relevant for CF. A hybrid reference that combined whole genome sequencing (WGS) from 101 CF individuals with the 1KG imputed a greater number of single-nucleotide variants (SNVs) that would be analyzed in a genetic association study (r2 ≥ 0.3 and MAF ≥ 0.5%) than imputation with the HRC, while the HRC excelled in the lower frequency spectrum. Using the 1KG or HRC as reference panels missed the most common CF-causing variants or displayed low imputation accuracy. Designs that incorporate population-specific WGS can improve imputation accuracy at disease-specific loci, while imputation using public data sets can omit disease-relevant genotypes.